Very Long Chain Fatty Acid Synthesis is a Metabolic Dependency and Therapeutic Target in NRAS Mutant Leukemia

Identification of therapeutic targets is hindered by a lack of clinically relevant models and amenable ex vivo platforms. We utilize a bone marrow endothelial cell co-culture system to perform CRISPR/Cas9 screens on wild-type cells and isogenic leukemias with and without oncogenic Nras.

We identified Elovl1, a very long chain fatty acid (VLCFA) elongase, as an Nras selective leukemic dependency, both ex vivo and in vivo. Genetic studies in primary leukemias revealed the fitness defect from Elovl1 loss comes in part from disruption of sphingomyelin production, as sgRNAs targeting Sgms1 phenocopy Elovl1 loss. Sphingomyelin is an essential sphingolipid necessary for generating lipid rafts, key concentrating scaffolds for multiple signaling pathways required in Nras mutant AML.